Stereolability of dihydroartemisinin, an antimalarial drug: a comprehensive kinetic investigation. Part 2

Artemisinin or qinghaosu has now largely given way to the more potent dihydroartemisinin (DHA, 1) and its derivatives in the treatment of drug-resistant malaria, in combination with other classical antimalarial drugs. DHA is obtained by NaBH(4) reduction of artemisinin and contains a stereochemically labile center at C-10, which provided two lactol hemiacetal interconverting epimers, namely 1α and 1β. In the solid state, the drug consists exclusively of the β-epimer; however, upon dissolution, the two epimers equilibrate, reaching different solvent-dependent ratios with different rates. Such equilibration also occurs in vivo, irrespective of the isomeric purity at which the drug would have been administered. The aim of this study was then to achieve an in-depth understanding of the kinetic features of the α/β equilibration. To this purpose, free energy activation barriers (ΔG(?)) of the interconversion were determined as a function of both general and specific acid and base catalysts, ionic strength, and temperature in different solvents by dynamic HPLC (DHPLC). In hydro-organic media, the dependence of ΔG(?) on temperature led to the evaluation of the related enthalpic and entropic contributions. Theoretical calculations suggested that the rate-determining step of the interconversion is not the ring-opening of the cyclic hemiacetal but the previous reversible deprotonation of the individual epimers (base-catalyzed mechanism). The whole findings may contribute to shed some light on the mechanism of action and/or bioavailability of the drug at the molecular level.     

Alkylation of heme by artemisinin,an antimalarial drug

The reductive activation of artemisinin (or artemether) by ferroprotoporphyrin-IX, the prosthetic group of hemoglobin, is able to produce covalent adducts heme-artemisinin in high yield under very mild conditions. This adduct formation, using the natural target of an endoperoxide antimalarial drug, confirms the alkylating ability of this class of antimalarial drugs, which has already been reported when using a synthetic manganese porphyrin.     

Conversion of antimalarial drug artemisinin to a new series of tricyclic 1,2,4-trioxanes1

A highly efficient route for the conversion of the antimalarial drug artemisinin to a novel hydroxy-functionalized tricyclic 1,2,4-trioxane 6 is reported. Neither the trioxane 6 nor its derivatives 14-16, all of which lack the hydrolytically unstable acetal-lactone linkage, show antimalarial activity comparable with that of artemisinin.     

Reactions of Alkenediazonium Salts. Part 1. 2,2-Diethoxyethene-diazonium hexachloroantimonate: A diazonium,a carbenium or an oxonium salt?

Reactions of the title compound 1 with various nucleophiles have been studied. The salt behaves like an alkylating agent towards ethers, alcohols and water forming ethyl diazoacetate ( 2 ), which reacts further with excess of the nucleophile. A solvent cage mechanism accounting for the observed products is proposed. Thermal decomposition in inert solvents leads to the alkylation of the counter-ion, i.e. formation of chloroethane, and in anisole, alkylation and chlorination of the solvent are also observed. With a standard coupling component, 2-naphtholate ion, no azo coupling reaction of 1 is observed, but instead 14-methyl-14 H-dibenzo[a,j]xanthene ( 17 ) is formed. The products of the reaction with diethylamine are diethylcyanoformamide ( 18 ) and ethyl diethylcarbamate ( 19 ). None of the chemistry of salt 1 is explained by the intervention of vinyl cations expected to be formed in a heteroytic dediazoniation. The predominant pathways seem to involve reactions of an oxonium salt (alkylating properties) or, in the case of diethylamine, a carbenium salt (primary nucleophilic attack on the β-C-atom of 1 ). The free energy barrier to C?C rotation in 1 is estimated to be 75 to 77 kJ/mol (18.0 to 18.5 kcal/mol), a value which falls between those expected for a double and a single bond.     

Cocrystals of the antimalarial drug 11‐azaartemisinin with three alkenoic acids of 1:1 or 2:1 stoichiometry

The stoichiometry, X‐ray structures and stability of four pharmaceutical cocrystals previously identified from liquid‐assisted grinding (LAG) of 11‐azaartemisinin (11‐Aza; systematic name: 1,5,9‐trimethyl‐14,15,16‐trioxa‐11‐azatetracyclo[10.3.1.0^4,13.0^8,13]hexadecan‐10‐one) with trans‐cinnamic (Cin), maleic (Mal) and fumaric (Fum) acids are herein reported. trans‐Cinnamic acid, a mono acid, forms 1:1 cocrystal 11‐Aza:Cin ( 1 , C₁₅H₂₃NO₄·C₉H₈O₂). Maleic acid forms both 1:1 cocrystal 11‐Aza:Mal ( 2 , C₁₅H₂₃NO₄·C₄H₄O₄), in which one COOH group is involved in self‐catenation, and 2:1 cocrystal 11‐Aza₂:Mal ( 3 , 2C₁₅H₂₃NO₄·C₄H₄O₄). Its isomer, fumaric acid, only affords 2:1 cocrystal 11‐Aza₂:Fum ( 4 ). All cocrystal formation appears driven by acid–lactam R₂²(8) heterosynthons with short O—H…O=C hydrogen bonds [O…O = 2.56 (2) Å], augmented by weaker C=O…H—N contacts. Despite a better packing efficiency, cocrystal 3 is metastable with respect to 2 , probably due to a higher conformational energy for the maleic acid molecule in its structure. In each case, the microcrystalline powders from LAG were useful in providing seeding for the single‐crystal growth.     

Poly(D,L-lactide-co-glycolide)/hydroxyapatite core-shell nanospheres. Part 3: properties of hydroxyapatite nano-rods and investigation of a distribution of the drug within the composite

A step-by-step analysis of the formation and the drug loading of the poly(D,L-lactide-co-glycolide)/hydroxyapatite (PLGA/HAp) composite was carried out in a perspective of the following parameters: the structure, the morphology and the adsorption/desorption properties of the composite's bioceramic part. The authors demonstrated the importance of the material's capacity to form a fine dispersion of solid HAp particles, as an initial step, for the further loading of the drug and for the formation of the core-shell structures. The nanometer-sized rods of HAp have the capacity of ensuring a rapid adsorption and a controlled desorption of the drug from their surface, and they can act as a nucleating site for the formation of polymeric cores. Each component of this material was labeled with fluorescence dye, which enabled an insight into the distribution of the components in the core-shells that were obtained as the final outcome. Such an analysis showed a high level of uniformity among the cores enclosed within polymeric shells. From a practical perspective, the labeling of each component of the composite can be regarded as an additional functionality of the material: labeling can enable us to monitor its action during the healing process. This ability to be easily detected is expected to enhance the procedure for the controlled delivery of antibiotics after their local implantation of carriers loaded with the antibiotic and to provide more careful control over this process.     

Comparative protein modeling of 1-deoxy-D-xylulose-5-phosphate reductoisomerase enzyme from Plasmodium falciparum: a potential target for antimalarial drug discovery

Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Pf-DXR) is a potential target for antimalarial chemotherapy. The three-dimensional model (3D) of this enzyme was determined by means of comparative modeling through multiple alignment followed by intensive optimization, minimization, and validation. The resulting model demonstrates a reasonable topology as gauged from the Ramachandran plot and acceptable three-dimensional structure compatibility as assessed by the Profiles-3D score. The modeled monomeric subunit consists of three domains: (1) N-terminal NADPH binding domain, (2) connective or linker domain (with most of the active site residues located in this domain), and (3) a C-terminal domain. This structure proved to be consistent with known DXR crystal structures from other species. The predicted active site compared favorably with those of the templates and appears to have an active site with a highly conserved architecture. Additionally, the model explains several site-directed mutagenesis data. Besides using several protein structure-checking programs to validate the model, a set of known inhibitors of DXR were also docked into the active site of the modeled Pf-DXR. The docked scores correlated reasonably well with experimental pIC50 values with a regression coefficient (R2) equal to 0.84. Results of the current study should prove useful in the early design and development of inhibitors by either de novo drug design or virtual screening of large small-molecule databases leading to development of new antimalarial agents.     

Poly(D,L-lactide-co-glycolide)/hydroxyapatite core-shell nanospheres. Part 1: A multifunctional system for controlled drug delivery

Biodegradable poly(d,l-lactide-co-glycolide) (PLGA) and bioactive hydroxyapatite (HAp) are selected for the formation of a multifunctional system with the specific core-shell structure to be applied as a carrier of a drug. As a result, both components of PLGA/HAp core-shells are able to capture one part of the drug. Polymeric shells consisting of small nanospheres up to 20nm in size act as a matrix in which one part of the drug is dispersed. In the same time, ceramic cores are formed of rod-like hydroxyapatite particles at the surface of which another part of the drug is adsorbed onto the interface between the polymer and the ceramics. The content of the loaded drug, as well as the selected solvent/non-solvent system, have a crucial influence on the resulting PLGA/HAp morphology and, finally, unimodal distribution of core-shells is obtained. The redistribution of the drug between the organic and inorganic parts of the material is expected to provide an interesting contribution to the kinetics of the drug release resulting in non-typical two-step drug release.     

The chemical reactivity of a known anti-psoriasis drug. Part 1: Further insights into the products resulting from oxidative cleavage

The oxidative cleavage of the known anti-psoriasis drug 1 to give 2 has been reported previously. Due to the importance of accessing medium-sized ring containing systems via oxidative cleavage, this reaction has been revisited revealing additional information about the structure of 2. Alternative reaction products were identified when the reaction was carried out in the presence of water. The conversion of 1 to 2 has also been carried out using ruthenium tetroxide. A detailed variable temperature NMR and computational study of the restricted rotation of the N-aryl ring in 2 is presented.     

Application of thermal analysis to the study of anti-tuberculosis drug compatibility. Part 1

Worldwide Brazil is among one of the 22 countries with high rates of tuberculosis placing this disease as a priority for the Government Health Policies in this country. Studies with the main tuberculostatic drugs rifampicin, isoniazid, pyrazinamide, and ethambutol, aiming the development of fixed-dose combination formulations (FDCs) have been performed. The aim of this study was to evaluate the thermal behavior of these drugs by DSC, TG/DTG, and DTA in order to predict possible physical and chemical interactions between tuberculostatics. DSC and DTA curves suggested incompatibility and/or interactions among drug preparations resulting from new thermal events, as well as the disappearance and shift of the melting point of the drugs. TG/DTG curves of drug mixtures presented different profiles from those observed for the individually tested drugs, supporting the evidence of drug incompatibility and indicating that mixtures are less stable when compared to the drugs alone.     

A systematic investigation of aluminium ion speciation at high temperature. Part 1. Solution studies

Speciation diagrams of aluminium ions in aqueous solution (0.2 M) at high temperature (90 degrees C) have been obtained from 48 h time-resolved multi-batch titration experiments monitored by 27Al NMR spectroscopy, potentiometry and dynamic light scattering. The quantitative speciation patterns and kinetic data obtained offer a dynamic picture of the distribution of soluble and insoluble Al species as a function of hydrolysis ratio h(h=[OH-]/[Al3+]) over a very broad range of conditions (-1.0 < or =h < or = 4.0). Monomeric, small oligomeric, tridecameric (the 'Al13-mer') and the recently characterised 30-meric aluminium species (the 'Al30-mer') as well as aluminium hydroxide have been identified and quantified. The Al13-mer species dominates over a relatively broad range of hydrolysis ratios (1.5 < or =h< or = 2.7) during the first 6 h of experiment, but are gradually replaced by Al30-mers at longer reaction times. Kinetic profiles indicate that the formation of the Al30-mer is limited by the disappearance of the Al13 species at mildly acidic conditions. The estimated rate constants of both hydrolytic processes show good internal correlation at h> or = 1.5. The effect of local perturbations leading to the formation of aluminium hydroxide below the electroneutrality point (h= 3.0) has been estimated quantitatively.     

Multistate/multifunctional systems. A thermodynamic,kinetic, and photochemical investigation of the 4'-dimethylaminoflavylium compound

The 4'-dimethylaminoflavylium ion in aqueous solution undergoes an intricate network of chemical reactions controlled by pH and light excitation. It is shown that nine different forms are involved, including two species that are not present in previously investigated compounds of the flavylium family. The thermodynamic and kinetic constants of the equilibria and interconversion processes have been obtained by pH jump (included stopped-flow) experiments. The photochromic properties exhibited by the trans/cis chalcone forms have been investigated. The peculiar aspect of 4'-dimethylaminoflavylium, as compared to previously investigated compounds of the same family, is a close to planarity structure, as demonstrated by the X-ray analysis on the parent 4'-aminoflavylium compound (2.3 degrees torsion angle between the benzopyrylium and benzene ring). The results obtained show that the flavylium cation is strongly stabilized by the electron-donor character of the dimethylamino substituent on the benzene ring. The donor-acceptor interaction makes both the protonation of the amino group and the hydration of the flavylium cation difficult, with consequences on the tautomerization and cis/trans isomerization reactions. The multistate/multifunctional properties of 4'-dimethylaminoflavylium have been discussed in the frame of write-lock-read-unlock-erase cycles.     

Molecular recognition of sulfonatocalixarene with organic cations at the self-assembled interface: a thermodynamic investigation

A microcalorimetric study on molecular recognition of p-sulfonatocalix[4]arene derivatives at selfassembled interface in comparison with in bulk water was performed,inspired by the dramatic change in physicochemical characteristics from bulk water to interface.A total of six cationic molecules were screened as model guests,including ammonium(NH_4~+),guanidinium(Gdm~+).N,N'-dimethyl-1,4-diazabicyclo[2.2.2]octane(DMDABCO~(2+)),tropylium(Tpm~+),N-methyl pyridinium(N-mPY*) and methyl viologen(MV~(2+)).The complexation with NH_4~+.Gdm~+ and DMDABCO2* is pronouncedly enhanced when the recognition process moved from bulk water to interface,whereas the complexation stabilities with Tpm~+,N-mPY~+ and MV2* increase slightly or even decrease to some extent.A more interesting phenomenon arises from the NH_4~+/Gdm~+ pair that the thermodynamic origin at interface differs definitely from each other although with similar association constants.The results were discussed in terms of differential driving forces,electrostatic,hydrogen bond as well as π-stacking interactions,originating from the unique physicochemical features of interfaces,mainly the polarity and dielectric constant.     

Electronic structure and conformational analysis of P218: An antimalarial drug candidate

P218 is one of the very important and recent lead compounds for antimalarial research. The 3D structural and electronic details of P218 are not available. In this article, quantum chemical studies to understand the possible 3D structures of P218 are reported and compared with 3D structures from the active site cavities of hDHFR and PfDHFR. The neutral P218, can adopt open chain as well as cyclic arrangements. Under implicit solvent condition a zwitterionic‐cyclic conformer is found to be quite possible. Microsolvation studies using explicit water molecules indicate that one water molecule may bridge the two ends of zwitterionic‐cyclic P218. It was observed that the protonation occurs preferentially at N¹ position of the 2,4‐diaminopyrimidine ring, with a proton affinity of 274.49 kcal/mol (implicit solvent phase) and 236.35 kcal/mol (gas phase). A dimer of P218 may be zwitterionic dimer, the dimer formation can release upto ～28.60 kcal/mol (implicit solvent phase).